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Evidence for the Involvement of the Kainate Receptor Subunit Glur6 (GRIK2) in Mediating Behavioral Displays Related to Behaviora

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Evidence for the Involvement of the Kainate Receptor Subunit Glur6 (GRIK2) in Mediating Behavioral Displays Related to Behaviora Molecular Psychiatry (2008) 13, 858–872 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp ORIGINAL ARTICLE Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania G Shaltiel1, S Maeng1, O Malkesman1, B Pearson1, RJ Schloesser1, T Tragon1, M Rogawski2, M Gasior2, D Luckenbaugh1, G Chen1 and HK Manji1 1Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; 2Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with bipolar disorder (BPD), but its function in affective regulation is unknown. Compared with wild-type (WT) and GluR5 knockout (KO) mice, GluR6 KO mice were more active in multiple tests and super responsive to amphetamine. In a battery of specific tests, GluR6 KO mice also exhibited less anxious or more risk-taking type behavior and less despair-type manifestations, and they also had more aggressive displays. Chronic treatment with lithium, a classic antimanic mood stabilizer, reduced hyperactivity, aggressive displays and some risk-taking type behavior in GluR6 KO mice. Hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. The membrane levels of other glutamatergic receptors were not significantly altered by GluR6 ablation or chronic lithium treatment. Together, these biochemical and behavioral results suggest a unique role for GluR6 in controlling abnormalities related to the behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggressiveness, driven or increased goal-directed pursuits, risk taking and supersensitivity to psychostimulants. Whether GluR6 perturbation is involved in the mood elevation or thought disturbance of mania and the cyclicity of BPD are unknown. The molecular mechanism underlying the behavioral effects of lithium in GluR6 KO mice remains to be elucidated. Molecular Psychiatry (2008) 13, 858–872; doi:10.1038/mp.2008.20; published online 11 March 2008 Keywords: glutamate receptor 6 (GluR6); kainate receptors (KARs); mood-related behaviors; bipolar disorder (BPD); knockout mice (KO); lithium Introduction behavior, increased goal-directed behavior, increased pursuit of pleasurable activities with potentially Bipolar disorder (BPD) (also known as manic-depres- painful consequences and substance abuse. Episodes sive illness) is one of the most severely debilitating of depression are characterized by depressed or medical illnesses, affecting the lives and functioning irritable mood accompanied by markedly diminished of millions worldwide.1 Emerging data suggest that interest or pleasure in everyday activities, psycho- BPD arises from the complex inheritance of multiple motor agitation or retardation, changes in body weight susceptibility genes.2–4 Phenotypically, it is a very or appetite, poor memory and concentration, fatigue complex disease in which patients alternate between and recurrent thoughts of death or suicide.1 episodes of mania and depression. Manic episodes There is a growing appreciation that BPD can be are characterized by euphoric or irritable mood, best conceptualized as a genetically influenced dis- thought disturbances, such as racing thoughts and order of synapses and circuits. It is thus noteworthy grandiosity, and behavioral symptoms, including that recent human genetic studies have identified hyperactivity, poor judgment, recklessness, aggressive GRIK2 (which encodes for GluR6, a kainite receptor implicated in synaptic plasticity) as a potential BPD 5 Correspondence: Dr HK Manji, Chief, Laboratory of Molecular susceptibility gene. Genetic linkage of BPD to Pathophysiology, National Institute of Mental Health, National chromosome 6q21 has been demonstrated in several Institutes of Health, Bldg. 35, Room 1C-912, 35 Convent Drive studies, and genome-wide significant linkage was MSC-3711, Bethesda, MD 20892, USA. recently established by meta-analysis.6–9 Buervenich E-mail: [email protected] Received 11 August 2007; revised 17 December 2007; accepted 20 and colleagues investigated the broad linkage peak on December 2007; published online 11 March 2008 6q and found that a specific haplotype, located on the GluR6 regulates mania-related behaviors G Shaltiel et al 859 regulatory region of the human GluR6 gene, was asso- behaviors in GluR6 KO mice, a series of biochemical ciated with BPD. In addition, very recent post-mortem studies were also conducted. studies demonstrate a reduction in GluR6 mRNA levels in the brains of BPD patients,10 thus pointing to GluR6 as a potential candidate gene in the patho- Materials and methods physiology of BPD. Animals A completely independent genetic study has also recently implicated the GRIK2 gene in a behavioral KAR KO mice were originated from 129/Sv and C57/ phenotype that may be associated with BPD.11 Bl6 background, and then backcrossed with 129Sv/Ev mice for at least 10 generations to provide an isogenic Intriguingly, the very same gene has been found to 25 confer sensitivity to treatment-emergent suicidal 129Sv/Ev strain. GluR6 KO, GluR5 KO and WT male mice, aged 8 weeks old, were single housed in an ideation in a large collaborative genetic study of ± 1 individuals with mood disorders (Sequenced Treat- animal room at a constant temperature (22 1 C) and ment Alternatives to Relieve Depression (STAR*D)).11 a 12-h light/dark cycle with free access to food and Individuals with variations in genes encoding GluR6 water. Female mice were not used in the studies and GluR3 (an AMPA receptor) were 15 times more to avoid the potential confounding effects of the likely to experience treatment-induced suicidal menstrual cycle on behavioral and neurochemical ideation. Although the neurobiologic basis of this measures. Mice were subjected to multiple tests in the following sequence designed from less to more very rare (but serious) side effect is unknown, it is 26 noteworthy that individuals with BPD—and poten- intrusive as recommended previously: open-field, tially those with a bipolar diathesis—are susceptible social interaction, elevated plus maze, forced swim, to antidepressant-induced dysphoric activation/agita- resident–intruder, saline–response and psychostimu- tion and potential suicidality.12,13 lant–response tests. The tests were performed at least Among the ionotropic glutamate receptors are the 24 h apart. Additional cohorts of mice were used for kainate receptor (KAR) family comprising five sub- other behavioral evaluations, such as passive avoid- units: GluR 5–7 and KA-1-2 (also named glutamate ance test, and for experiments with lithium treatment. receptor ionotropic kainate (GRIK) 1–5, respectively). Mice to be compared were tested concurrently in KARs are expressed in the areas of neuronal circuits the same room under dim illumination (30 lux) by involved in mood regulation.14,15 They have been the same testers between 10:00 and 18:00 hours. shown to bidirectionally regulate the release of gluta- All experimental procedures were approved by the mate at the mossy fiber to CA3 synapses,16 and Animal Use Committee of the National Institute of notably, they are also involved in long-term poten- Mental Health (NIMH) and were conducted according tiation induction at the hippocampus and the to the National Institutes of Health guidelines. amygdala.17 Moreover, it is now widely accepted that presynaptic KARs control the release of GABA Passive avoidance test (g-aminobutyric acid) in the hippocampus and The test was conducted as described previously by the amygdala.16,18 Furthermore, a growing body of El-Ghundi,27 with the modification of using GEMINI evidence demonstrates that KARs have metabotropic Avoidance System driven by in-house software. In actions in addition to their ionotropic activity that brief, all mice were given one habituation trial to modulates both hippocampal inhibitory19 and excita- explore both chambers for 120 s, followed by two tory postsynaptic currents20 as well as pyramidal training trials separated by 5 min. During the training cell excitability.21,22 The metabotropic actions include trials, individual mice were placed in the bright interaction with G proteins, induction of second chamber for 30 s, after which a guillotine door was messengers and activation of PKA (protein kinase A), opened and the latency to enter the dark chamber was PKC (protein kinase C) and MAP (mitogen-activated measured for 300 s. On the second trial, on entrance protein) kinases.19–22 into the dark compartment (all four paws and In view of the GluR6 receptor as a putative BPD tail inside), the guillotine door was closed and the susceptibility gene, we undertook a series of animal mouse was confined in the dark compartment for studies to elucidate the role of this receptor in modu- 10 s, followed by two consecutive 3-s (inescapable) lating behavioral patterns related to facets of the foot shocks (0.6 mA), left in the compartment for an complex symptoms of BPD. Furthermore, to deter- additional 10 s, and then returned to their home cage mine potential specificity of this receptor to mood- and left there undisturbed until the next acquisition related behaviors, we also investigated the role of
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